REVIEW ARTICLE &XUUHQW3UHYHQWLRQDQG0DQDJHPHQWRI1RQVWHURLG $QWL,QÀDPPDWRU\'UXJV$VVRFLDWHG*DVWURHQWHURSDWK\ Fransiscus Ari*, Dadang Makmun** *Department of Internal Medicine, Faculty of Medicine, University of Indonesia Dr. Cipto Mangunkusumo General National Hospital, Jakarta **Division of Gastroenterology, Department of Internal Medicine University of Indonesia/Dr. Cipto Mangunkusumo General National Hospital, Jakarta ABSTRACT 1RQVWHURLGDQWLLQÀDPPDWRU\GUXJV 16$,'V DUHWKHPRVWIUHTXHQWO\XVHGGUXJVWRWUHDWLQÀDPPDWLRQ and are used almost in the whole world. However, NSAID is one of the important causes of gastroenteropathy development. NSAIDs enteropathy is frequently undetected because most of them are asymptomatic and required sophisticated examinations to diagnose. Not only non-selective cyclo-oxygenases (COX) inhibitor that can cause NSAID gastropathy, but selective COX-2 inhibitors may also cause gastrointestinal complications. NSAID gastroenteropathy require further evaluation and it may differ between patients. Currently, there is no effective treatment available to treat gastrointestinal damage associated with NSAIDs DGPLQLVWUDWLRQ,GHQWL¿FDWLRQRISURWHFWLYHIDFWRUVLQJDVWURLQWHVWLQDOFRPSOLFDWLRQGXHWR16$,'VXVHLVVWLOOD serious challenge. In this review, we will discuss the effect of NSAID administration towards gastrointestinal system, also the prevention and management strategies. Keywords: QRQVWHURLGDQWLLQÀDPPDWRU\GUXJVJDVWURHQWHURSDWK\&2;LQKLELWRUSUHYHQWLRQWUHDWPHQW ABSTRAK 2EDWDQWLLQÀDPDVLQRQVWHURLG 2$,16 DGDODKREDW\DQJSDOLQJVHULQJGLJXQDNDQXQWXNWHUDSLLQÀDPDVL dan digunakan hampir di seluruh dunia. Namun, OAINS merupakan salah satu penyebab penting terjadinya gastroenteropati. Enteropati OAINS seringkali tidak terdeteksi karena sebagian besar asimtomatik dan membutuhkan pemeriksaan yang canggih untuk mendiagnosisnya. Tidak hanya penghambat cyclo-oxygenases (COX) non-selektif yang menjadi penyebab gastropati OAINS, melainkan inhibitor COX-2 selektif dapat menimbulkan komplikasi gastrointestinal. Gastroenteropati OAINS membutuhkan pengkajian lebih lanjut dan berbeda antar pasien. Sampai saat ini belum ada terapi yang efektif untuk kerusakan gastrointestinal terkait penggunaan OAINS. ,GHQWL¿NDVLGDULIDNWRUIDNWRUSURWHNWLISDGDNRPSOLNDVLJDVWURLQWHVWLQDODNLEDWSHQJJXQDDQ2$,16PDVLK merupakan tantangan yang serius. Dalam makalah ini dibahas mengenai efek penggunaan OAINS terhadap sistem gastrointestinal serta strategi pencegahan dan tatalaksananya. Kata kunci: REDWDQWLLQÀDPDVLQRQVWHURLGJDVWURHQWHURSDWLSHQJKDPEDW&2;SHQFHJDKDQWDWDODNVDQD INTRODUCTION therapy is elderly with higher morbidity and mortality 1RQVWHURLGDQWLLQÀDPPDWRU\GUXJV 16$,'V LV towards the occurrence of drug toxicity effect.2 the most frequently prescribed drug group in the world.1 NSAIDs are used widely to treat clinical symptoms The main population target which often receive this LQLQÀDPPDWRU\FRQGLWLRQDQGDOVRWRRYHUFRPHSDLQ Volume 15, Number 3, December 2014 161 Fransiscus Ari, Dadang Makmun Additionally, low dose aspirin (acetylsalicylate acid or 16$,'6 *$6752(17(523$7+<3+<6,2/2*< ASA) is used for primary and secondary prevention $63(&7 of cerebrovascular and cardiovascular diseases.3 This 1RQVWHURLGDQWLLQÀDPPDWRU\GUXJV 16$,'V FDQ group of drugs inhibit prostaglandin biosynthesis to EHFODVVL¿HGLQWRVHYHUDOJURXSVEDVHGRQWKHFKHPLFDO produce therapeutic effects.4 structure and mechanism of action (Table 1). This Main adverse effects in NSAIDs administration GUXJGHFUHDVHVSDLQDQGLQÀDPPDWLRQWKURXJKWKH include disturbance in the gastrointestinal, nervous blocking of cyclo-oxygenases (COX), enzyme required system, kidney, and allergy. NSAIDs toxicity towards for prostaglandin production. Most NSAIDs inhibit gastrointestinal has been widely known, particularly in two cyclo-oxygenases, which are COX-1 and COX- gastroduodenal region.2 Gastrointestinal disturbances 2.3 COX-2 enzymes are mostly found in joints and which happen vary from dyspepsia complaints muscles and contribute to the appearance of pain and to gastroduodenal ulcer and bleeding.1 NSAIDs LQÀDPPDWLRQ16$,'VPD\FDXVHEOHHGLQJGXHWRWKH gastropathy (aspirin) is initially found by Douthwaite effect of these drugs in inhibiting COX-1 enzyme that DQG/LQWRWWLQWKURXJKHQGRVFRS\¿QGLQJV5 A is important in mucosal protection towards gastric acid. meta-analysis study showed, based on endoscopy Morbidity and mortality rate due to gastrointestinal examination, approximately one third patients who complication in the use of NSAIDs increase along with received long term NSAID had gastric or duodenal the increase of age (Table 2).11 Besides age, there are ulcer.6 other several risk factors which have high risk in the Based on data from Arthritis, Rheumatism, and occurrence of gastrointestinal complications, including Aging Medical Information System (ARAMIS), there previous peptic ulcer history, Helicobacter pylori were 1.3% patients who were treated with NSAID (H. pylori)LQIHFWLRQLQWKH¿UVWPRQWKRI16$,'V were hospitalized due to severe gastrointestinal administration, high dose NSAID usage, and other complications in USA and Canada population, with comorbid conditions (particularly cardiovascular), and 1 year mortality rate ranges between 0.11-0.22%.7 the use of anticoagulants and corticosteroid.1 Based on other reports, gastric erosion is found in 50% patients consuming NSAIDs, with 2-4% from Table 2. Risk of gastrointestinal bleeding in 1 year administration WKLVJURXSVXIIHUHGIURPVLJQL¿FDQWJDVWURLQWHVWLQDO of NSAIDs11 ulcer and bleeding.8 Meanwhile, in a patient autopsy Age group Bleeding risk Mortality rate due data based study, patients who use long term NSAIDs (Years old) 5LVNLQ\HDULVLQ to bleeding 16-45 2100 12353 had the incidence of small intestinal ulcer of 8% as 45-64 646 3800 compared to 0.6% in patients who had no history of 65-74 570 3353 >75 110 647 NSAIDs administration.9 Enteropathy due to the use of NSAIDs received less attention because they usually caused no symptoms and are not easy to detect.10 7DEOH16$,'VFODVVL¿FDWLRQ4 Types Chemical components General name of drugs Salicylates Second generation - hydroxybenzoic acid $VSLULQGLÀXQLVDODQGVDOVDODWH (salicylic acid) Proprionate acid “profens” derivatives Derivatives of arylacetic acids Ibuprofen, dexibuprofen, ketoprofen, dexketoprofen, naproxen, fenoprofen, ÀXUELSURIHQR[DSUR]LQDQGOR[RSURIHQ Acetic acid derivatives Acetic acid derivatives Indomethacin, diclofenac, nabumetone, tolmetin, sulindac, etodolac, and ketorolac Derivatives of Enolic acid “oxicams” Fourth generation-hydroxy benzothiazine Piroxicam, isoxicam, meloxicam, Heterocycle tenoxicam, droxicam, and lornoxicam Derivatives of Fenamic acid “fenamates” Derivatives of anthranilic acid 0HIHQDPLFDFLGÀXIHQDPLFDFLG tolfenamic acid, and meclofenamic acid Phenylpyrazolones First generation-aryl-3,5- Phenylbutazone, oxyphenbutazone Pyrazolidinedione Selective COX-2 inhibitor Diaryl-5-membered heterocycles Celecoxib, rofecoxib, and valdecoxib Anilides and Sulphoanilides Acetamides from aniline with or without Acetaminophen, phenacetin, and 4-hydroxy or 4-alkoxy nimesulide 162 The Indonesian Journal of Gastroenterology, Hepatology and Digestive Endoscopy Current Prevention and Management of Non Steroid Anti Inflammatory Drugs Associated Gastroenteropathy NSAIDs, including aspirin, cause damage to the increase leukotriene production. Leukotriene may gastric mucosa through two mechanisms, which are: VWLPXODWHLQÀDPPDWLRQDQGWLVVXHLVFKHPLDZKLFK systemic inhibition of endogenous prostaglandin cause the occurrence of gastric mucosal damage. synthesis in the mucosa and direct irritation or )XUWKHUPRUHRWKHULQÀDPPDWRU\PHGLDWRUVLQFOXGLQJ topical effect to the gastric epithelium. Inhibition of tumour necrosis factors are also increased. endogenous prostaglandin synthesis in the mucosa is Damage to the small intestinal mucosa (enteropathy) caused by inhibition of COX enzyme, which converts even until the bowel (colopathy) have different arachidonic acid into prostaglandin.12 This adverse pathophysiology to the damage of gastroduodenal effect occurs due to the non-selective feature of mucosa.14,15 The incidence of enteropathy have NSAIDs and inhibition of COX-1 enzyme, where the more complex pathophysiology and may proceed in DQWLLQÀDPPDWRU\UROHRIWKLVGUXJLVWKURXJK&2; much longer time compared to NSAIDs gastropathy. 2 enzyme inhibition. Currently, the use of selective Decrease of prostaglandin synthesis due to NSAIDs COX-2 (such as celecoxib) has been reported to have use resulted in fragile small intestinal mucosa towards weaker gastrointestinal effect. However, the use of damage and the process of mucosal recovery also selective COX-2 inhibitor also causes gastrointestinal decreases. However, different from what happened in complication. Hypothesis which explain this is that NSAIDs gastropathy, in enteropathy the suppression COX-2 also plays role in defence mechanism and of COX enzymes is not the main reason. Prostaglandin recovery process of damaged mucosa.13 in the intestinal mucosa can be suppressed but the NSAIDs also have direct cytotoxic effect to the ulcer or bleeding does not appear. The increase of gastric mucosa. Several studies showed that this mucosal permeability is caused by topical NSAIDs cytotoxic effect is not associated with inhibition irritation effect. The essential pathophysiology in ulcer activity of COX enzyme. Topical effect found in formation in the intestine is the presence of NSAIDs NSAIDs has acid characteristic (for example, aspirin), reabsorption in ileum and through enterohepatic which cause accumulation